Summary: Despite significant advances in modern medicine and drug discovery there are still tremendous unmet medical needs for combating human disease. Infectious diseases and neurodegenerative diseases contribute to global health and economic problems of significant magnitude. Traditional drug discovery efforts focused on protein inhibitors are now being complemented by more non-traditional approaches such as targeting protein-protein interactions, once considered undruggable targets. RNA and RNA-protein interactions represent further examples of non-traditional drug targets with significant potential. This is primarily due to the central role of RNA in a diverse array of biological processes ranging from information transfer (mRNA) and gene regulation (siRNA's and microRNA's) to catalysis (ribozymes and riboswitches). The siRNA pathway and the diverse world of non-coding RNA's have regulatory functions ranging from cellular differentiation and chromosomal organization to the regulation of gene expression. The ability to target RNA-dependent processes represents an important challenge at the frontier of human medicine. Although not often thought of as a target for drug discovery, RNA targeting has been very successful in the case of antibiotics such as the aminoglycosides, tetracyclines, and macrolide antibiotics. Despite these successes, our ability to rationally design molecules to target some of the most important RNA structural motifs with high affinity and specificity is essentially non- existent. This proposal aims to develop structure specific nucleic acid modulators for targeting unmet medical needs. We will apply our newly developed nucleic acid modulators to target RNA dependent processes in E. coli, a pathogen and model organism of great interest to human health and the NIH.